Targeted Strategies Directed at the Molecular Defect: Towards Precision Medicine for Select Primary Immunodeficiency Disorders

摘要

Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain of function (GOF) mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders moving beyond the more commonly seen loss of function mutations. The rapidly expanding genetic defects that have been identified in previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block over active or enhance under responsive cellular pathways. Selected primary immunodeficiences were chosen, whose genetic defects have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine forward.